Nobiletin-loaded micelles reduce ovariectomy-induced bone loss by suppressing osteoclastogenesis

Int J Nanomedicine. 2019 Sep 26:14:7839-7849. doi: 10.2147/IJN.S213724. eCollection 2019.

Abstract

Background: Nobiletin (NOB), a polymethoxy flavonoid, possesses anti-cancer and anti-inflammatory activities, has been reported that it played role in anti-osteoporosis treatment. However, previous research did not focus on practical use due to lack of hydrophilicity and cytotoxicity at high concentrations. The aim of this study was to develop a therapeutic formulation for osteoporosis based on the utilization of NOB.

Methods: In this study, NOB-loaded poly(ethylene glycol)-block-poly(e-caprolactone) (NOB-PEG-PCL) was prepared by dialysis method. The effects on osteoclasts and anti-osteoporosis functions were investigated in a RANKL-induced cell model and ovariectomized (OVX) mice.

Results: Dynamic light scattering and transmission electron microscopy examination results revealed that the NOB-PEG-PCL had a round shape, with a mean diameter around 124 nm. The encapsulation efficiency and drug loading were 76.34±3.25% and 7.60±0.48%, respectively. The in vitro release of NOB from NOB-PEG-PCL showed a remarkably sustained releasing characteristic and could be retained at least 48 hrs in pH 7.4 PBS. Anti-osteoclasts effects demonstrated that the NOB-PEG-PCL significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells stimulated by RANKL. Furthermore, the NOB-PEG-PCL did not produce cytotoxicity on bone marrow-derived macrophages (BMMs). The mRNA expressions of genetic markers of osteoclasts including TRAP and cathepsin K were significantly decreased in the presence of NOB-PEG-PCL. In addition, the NOB-PEG-PCL inhibited OC differentiation of BMMs through RANKL-induced MAPK signal pathway. After administration of the NOB-PEG-PCL, NOB-PEG-PCL prevented bone loss and improved bone density in OVX mice. These findings suggest that NOB-PEG-PCL might have great potential in the treatment of osteoporosis.

Conclusion: The results suggested that NOB-PEG-PCL micelles could effectively prevent NOB fast release from micelles and extend circulation time. The NOB-PEG-PCL delivery system may be a promising way to prevent and treat osteoporosis.

Keywords: TRAP; micelles; nobiletin; ovariectomized (OVX) mice.

MeSH terms

  • Animals
  • Bone Resorption / drug therapy*
  • Bone Resorption / etiology*
  • Cell Death / drug effects
  • Cytokines / metabolism
  • Drug Liberation
  • Female
  • Flavones / chemistry
  • Flavones / therapeutic use*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Micelles*
  • Osteoclasts / drug effects
  • Osteoclasts / pathology*
  • Osteogenesis* / drug effects
  • Osteoporosis / drug therapy
  • Ovariectomy / adverse effects*
  • Polyesters / chemistry
  • Polyethylene Glycols / chemistry
  • Signal Transduction / drug effects

Substances

  • Cytokines
  • Flavones
  • Micelles
  • Polyesters
  • polycaprolactone
  • Polyethylene Glycols
  • nobiletin